Hepatitis B accounts for approximately 5000 deaths/yr in the United States. Early results with orthotopic liver transplantation (OLT) for hepatitis B were poor with recurrence rates of >80% and 2-year mortality rates of 50%. Recent studies found that continuous high dose IV hepatitis B immune globulin (HBIG) can decrease the rate of reinfection to <20%. However, high dose HBIG is very expensive ($30,000-$50,000/yr) and the efficacy is low in patients with replicative infection pre-OLT. Pilot studies showed that lamivudine (LAM, an oral nucleoside analog which costs $1,200-$1,500 per yr) can decrease the rate of recurrent hepatitis B to <30% during the first post-OLT year but the long-term efficacy is limited by drug resistant mutants. Three pilot studies reported that combination therapy of HBIG and LAM is more effective than either agent alone with recurrence rates <5%, but it is not clear how long HBIG needs to be administered. Given the high costs and the inconvenience of life-long HBIG therapy, there is a need for a prospective, randomized controlled trial to determine if prophylaxis with LAM and short-term HBIG is as effective as LAM and long-term HBIG in the prevention of recurrent hepatitis B post-OLT. The use of antiviral agents with potential activity against LAM resistant HBV mutants, such as adefovir dipivoxil, also needs to be evaluated. The specific aims of our study are: (1) To compare the safety, efficacy and cost-effectiveness of combination therapy with LAM and a 6-month course of HBIG with LAM and a 3-yr course of HBIG in the prevention of recurrent hepatitis B post-OLT. (2) To identify the epidemiological, clinical and virological factors that are associated with recurrent hepatitis B post-OLT. (3) To determine the safety and efficacy of adefovir dipivoxil in the suppression of HBV replication in patients who have developed LAM resistant HBV mutants and to compare the rate of recurrent hepatitis B post-OLT in patients with and without LAM resistant mutants prior to transplant. This is a prospective, randomized, multi-center clinical trial involving 20 liver transplant centers in N. America, to be conducted under an investigator IND 59,167. 290 patients with hepatitis B who are listed for OLT as UNOS status 1 or 2 will be enrolled. Open label LAM will be administered to decrease virus load pre-OLT. Patients will be randomized after OLT to Group I: LAM and 3 yr-course of HBIG or Group II: LAM and 6-month course of HBIG. Patients who develop LAM resistant mutants pre- or post- OLT will additionally receive adefovir dipivoxil. The primary end-point of this trial is the rate of recurrent hepatitis B during the first 3 yr post-OLT. This trial will provide definitive answers whether combination therapy with LAM and a 6-mon course of HBIG is as efficacious and more cost-effective than LAM and a 3-yr course of HBIG in the prevention of recurrent hepatitis B post-OLT. In addition, crucial data will be generated on the efficacy of pre-OLT LAM in virus clearance, incidence and outcome of silent allograft infection, clinical outcome of patients with LAM resistant HBV mutants, and management of patients with LAM resistant mutants.